The present invention relates to a drug delivery system for the simultaneous release of two or more active substances and more particularly to a ring shaped vaginal drug delivery system, which system releases the active substances in a substantially constant ratio over a prolonged period of time.
Such release system is for example known from U.S. Pat. Nos. 3,995,633 and 3,995,634, where separate, preferably spherical or cylindrical, reservoirs containing different active substances are assembled in specially constructed holders. Such a release system is also described in U.S. Pat. No. 4,237,885, where a tube or coil of polymeric material is divided into portions by means of a plurality of "spacers" provided in the tube, after which each of the separate tube portions is filled with a different active substance in a silicone fluid and the two ends of the tube are subsequently connected to one another. In this release system, however, transport (diffusion) of active material from one reservoir to the other takes place through the wall of the tube, especially upon prolonged storage, so that the pre-set fixed release ratio between the active substances in question will change over a period of time.
A two-layered vaginal ring has been described in European patent publication 0,050,867 which ring comprises a pharmacologically acceptable supporting ring covered by two layers preferably of silicone elastomers whereby the inner layer is a silicone elastomer loaded with an active substance.
A similar ring shaped vaginal delivery system had been described in U.S. Pat. No. 4,292,965. The use of silicone elastomers is nowadays considered to be less safe and is clearly no longer the material of choice.
In U.S. Pat. No. 4,596,576 a two-compartment vaginal ring has been disclosed, wherein each compartment contains a different active substance. To achieve a suitable ring with a constant release ratio between the various active substances, it was necessary, however, to join the endportions of the compartments by inert stoppers, preferably glass stoppers.
Patent Publication WO 97/02015 discloses a two-compartments device, a first compartment consisting of a core, a medicated middle layer and a non medicated outer layer, and a second compartment consisting of a medicated core and a non medicated outer layer.
Release systems which over a lengthy period release two or more active substances in a substantially constant ratio to one another are extremely useful for certain applications. For example, in the field of contraception and in the field of hormone replacement therapy, extensive use is made of the simultaneous administration of an agent having a progestogenic activity and an agent having an estrogenic activity, preferably in a substantially constant ratio.
The simultaneous introduction of these two drugs into one reservoir can however only purely accidentally lead to the desired release ratio. In fact, the release per unit time is determined by the solubility of the active substance in the outer layer of polymeric material (which forms the wall of the reservoir) and by the diffusion coefficient of the active substance in that outer layer. In this type of release system, in fact, the choice of the outer layer material of the reservoir determines the release ratio of the active substances contained in the reservoir to a large extent.
Though theoretically it is possible to choose from among a very large variety of polymeric materials, it is found in practice that only a relatively small number of polymers seem to be capable of functioning satisfactorily as a release determining outer layer of the reservoir. Not only does the medical use impose certain requirements on the polymer but in addition a large number of polymers are unsuitable in that, for example, they possess insufficient rigidity, are insufficiently inert, provide insufficient solubility of the active substance(s), etc.
Moreover, the composition of the reservoir containing the active substances is likewise important because the reservoir material is responsible for an adequate supply of the active substances to the inner side of the outer layer. The reservoir material may not shrink upon release of the active substances, must be capable of taking up a large amount of the active substances, etc.
In most cases one is therefore forced to choose a release system with a plurality of separate reservoirs as a release system which is capable of releasing two or more active substances in a particular ratio as is clearly demonstrated in the above mentioned references. Apart from a not always satisfactory release, release ratio and release term in some cases, the disclosed vaginal rings all suffer from being relatively complicated, making them more expensive to manufacture.